DOCK8 deficiency is a combined immunodeficiency disease that has an unusual feature: patients have severe problems with recurrent and persistent infections of the skin. Their skin infections are caused by a wide variety of microbes. The microbes include bacteria that cause abscesses, and sometimes candida. However, the patients have the greatest problem controlling common viruses that infect the skin, such as herpes simplex virus, human papilloma virus, molluscum contagiosum virus, and varicella-zoster virus. These viruses can cause disfiguring, non-healing rashes if the patients are not treated with bone marrow transplantation. The patients also have other diseases of the skin, such as eczema caused by allergic inflammation, and skin cancers that are related to how extensive the viral skin infections are. A major goal of our program is to understand why the loss of DOCK8 in immune cells causes defective skin immunity. To do so, in work culminating in FY2015, we have studied T cells and NK cells from patients who are followed at the NIH Clinical Center. These cells are known to be especially important for antiviral immunity. By looking at the cells under the microscope, we discovered that they become misshapen and die when they move through skin or artificial environments that resemble skin. By studying a mouse model of DOCK8-deficiency during experimental herpes simplex virus infections of the skin, we also found that the memory T cells that normally reside in the skin where they patrol against viral infections, also die off. Our findings now explain an important aspect of skin immunity: that the immune cells must maintain their shape integrity when they travel through the tight meshwork that makes up the skin. This process is needed for the immune cells to survive and function properly, and its critical regulator is DOCK8. Understanding this has important implications for how immune cells function in other skin conditions. In FY2015, we also participated in a collaborative study related to autoimmunity in DOCK8 deficiency, which occurs infrequently but can be severe, for example affecting the large blood vessels in the brain. This study showed that the loss of DOCK8 results in defects in B cell tolerance in the periphery and in regulatory T cells, which could contribute to the autoimmunity. We also participated in an ongoing collaborative study focusing on improving hematopoietic stem cell transplantation for DOCK8 deficiency.